Publications

Journal Articles

Abstract

We have recently witnessed an explosion in our understanding of melanoma. Knowledge of the molecular basis of melanoma and the successes of targeted therapies have pushed melanoma care to the precipice of a new era. Identification of significant pathways and oncogenes has translated to the development of targeted therapies, some of which have produced major clinical responses. In this review, we provide an overview of selected key pathways and melanoma oncogenes as well as the targeted agents and therapeutic approaches whose successes suggest the promise of a new era in melanoma and cancer therapy. Despite these advances, the conversion of transient remissions to stable cures remains a vital challenge. Continued progress towards a better understanding about the complexity and redundancy responsible for melanoma progression may provide direction for anti-cancer drug development.

Abstract

Melanoma is one of the most aggressive and yet poorly understood of human malignancies. Advances in genomics has allowed a more nuanced understanding of the disease, moving beyond the traditional dysplastic nevus-to-melanoma model and identifying multiple divergent oncogenic pathways leading to melanoma. An understanding of the molecular mechanisms driving melanoma has opened the doors for the development of targeted therapeutic approaches. As we enter the era of personalized medicine, it will be critical for clinicians to both appreciate and be able to determine the molecular profile of their patients' melanoma because this profile will guide risk stratification, genetic counseling, and treatment customization. A review of the divergent pathways of melanoma development is presented here, with a particular emphasis on recently identified mutations, and their implications for patient care.

Abstract

Our current understanding of the relationship between psoriasis and psoriatic arthritis remains incomplete, though the evidence from the clinical setting, response to therapeutics, epidemiology, genetics, imaging, and immunopathologic models suggest that they make likely share a common pathogenesis. Psoriatic disease can no longer be thought of as a condition limited to skin and joints. Rather, it must be considered a multi-faceted disorder in which systemic inflammation plays a central role. There is now convincing evidence that individuals with psoriasis have a higher prevalence of co-morbid disease, particularly cardiovascular risk factors, metabolic disorders, and other immune-mediated inflammatory diseases. The cutaneous manifestations of psoriasis place dermatologists in a crucial and privileged role--one that affords us the potential for early detection of associated co-morbid conditions through screening and perhaps impact disease course and clinical outcomes.

Abstract

Concierge medical practice is a relatively new and somewhat controversial development in primary-care practice. These practices promise patients more personalized care and dedicated service, in exchange for an annual membership fee paid by patients. The experiences of patients using these practices remain largely undocumented.To assess the experiences of patients in a concierge medicine practice compared with those in a general medicine practice.Stratified random samples of patients empanelled to each of the four doctors who practice at both a general medicine and a concierge medicine practice separately situated at an academic medical center were drawn. Patients were eligible for the study if they had a visit with the physician between January and May 2006. The study questionnaire (Consumer Assessment of Healthcare Providers and Systems Clinician and Group Survey, supplemented with items from the Ambulatory Care Experiences Survey) was administered by mail to 100 general medicine patients per physician (n?=?400) and all eligible concierge medicine patients (n?=?201). Patients who completed the survey and affirmed the study physician as their primary-care physician formed the analytic sample (n?=?344) that was used to compare the experiences of concierge medicine and general medicine patients. Models controlled for respondent characteristics and accounted for patient clustering within physicians using physician fixed effects.Patients' experiences with organizational features of care, comprising care co-ordination (p?0.01), access to care (p?0.001) and interactions with office staff (p?0.001), favored concierge medicine over general medicine practice. The quality of physician-patient interactions did not differ significantly between the two groups. However, the patients of the concierge medicine practice were more likely to report that their physician spends sufficient time in clinical encounters than patients of the general medicine practice (p?0.003).The results suggest patients of the concierge medicine practice experienced and reported enhanced service, greater access to care, and better care co-ordination than those of the general medicine practice. This suggests that further study to understand the etiology of these differences may be beneficial in enhancing patients' experience in traditional primary-care practices.

Abstract

There are reports of rare adverse effects of tumor necrosis factor (TNF) inhibitors, including infections, malignancies, and induction of autoimmune conditions. Intriguing, are cases of induction or exacerbation of psoriasis in conjunction with TNF inhibitor therapy, given that they are approved for treatment of the same condition. Objective: Published cases of psoriasis occurring during anti-TNF therapy were analyzed, including overviews of proposed etiologies and treatment recommendations.A literature search using Ovid MEDLINE and PubMed was performed for articles published between January 1990 and September 2007 to collect reported cases of psoriasis in patients receiving therapy with TNF blocking agents.A total of 127 cases were identified: 70 in patients on infliximab (55.1%), 35 with etanercept (27.6%), and 22 with adalimumab (17.3%). Females comprised 58% of cases; mean age of reported patients was 45.8 years, and the time from initiation of treatment to onset of lesions averaged 10.5 months. These patients suffered from a number of primary conditions, with rheumatoid arthritis, ankylosing spondylitis, and Crohn's disease accounting for the vast majority. Palmoplantar pustular psoriasis was observed in 40.5% of the cases, with plaque-type psoriasis in 33.1%, and other types comprising the remainder. Topical corticosteroids were the most commonly employed treatment modality but led to resolution in only 26.8% of cases in which they were employed solely. Switching to a different anti-TNF agent led to resolution in 15.4% of cases. Cessation of anti-TNF therapy with systemic therapy led to resolution in 64.3% of cases.More information and cases are needed. Biopsies of TNF-blockade-induced lesions may reveal what cytokines and cell types drive the development of these lesions. Additionally, there is a need to develop an algorithm to treat this paradoxical side effect of therapy with TNF-blockers.

Abstract

Multiple synaptic adhesion molecules govern synapse formation. Here, we propose calsyntenin-3/alcadein-β as a synapse organizer that specifically induces presynaptic differentiation in heterologous synapse-formation assays. Calsyntenin-3 (CST-3) is highly expressed during various postnatal periods of mouse brain development. The simultaneous knockdown of all three CSTs, but not CST-3 alone, decreases inhibitory, but not excitatory, synapse densities in cultured hippocampal neurons. Moreover, the knockdown of CSTs specifically reduces inhibitory synaptic transmission in vitro and in vivo. Remarkably, the loss of CSTs induces a concomitant decrease in neuron soma size in a non-cell-autonomous manner. Furthermore, α-neurexins (α-Nrxs) are components of a CST-3 complex involved in CST-3-mediated presynaptic differentiation. However, CST-3 does not directly bind to Nrxs. Viewed together, these data suggest that the three CSTs redundantly regulate inhibitory synapse formation, inhibitory synapse function, and neuron development in concert with Nrxs.

Abstract

This study is the first double-blinded, randomized comparison of two absorbable sutures. To better understand product characteristics and surgeon preference, we conducted a study of two similar-appearing FDA-approved sutures, glyconate and poliglecaprone 25. Four dermatologic surgeons were enlisted. A total of 48 patients with 53 surgical sites were examined. One half of each surgical wound was closed with one type of suture and the other half with the other type. Each half was evaluated for product characteristics. There was no statistically significant difference in surgeon preference for glyconate versus poliglecaprone 25 (P=0.64). Of the cohort preferring poliglecaprone 25, there was a correlation with speed of closure (P=0.06). Of the surgeons that preferred glyconate, we found significantly better visibility (P=0.03), reduced suture breakage during knot tying (P=0.05), and correlation with better handling properties (P=0.06) associated with that preference. The data from this study will enable products to be designed towards these needs and allow surgeons to select sutures that more precisely fit their particular requirements.

Abstract

The purpose of this study was to prospectively assess the usefulness of computer-aided detection (CAD) in the interpretation of screening mammography and to provide the true sensitivity and specificity of this technique in a clinical setting.Over a 26-month period, 5,016 screening mammograms were interpreted without, and subsequently with, the assistance of the iCAD MammoReader detection system. Data collected for actionable findings included dominant feature (calcification, mass, asymmetry, architectural distortion), detection method (radiologist only, CAD only, or both radiologist and CAD), BI-RADS assessment code, associated histopathology for those undergoing biopsy, and tumor stage for malignant lesions. The study population was cross-checked against an independent reference standard to identify false-negative cases.Of the 5,016 cases, the recall rate increased from 12% to 14% with the addition of CAD. Of the 107 (2%) patients who underwent biopsy, 101 (94%) were prompted by the radiologist and six (6%) were prompted by CAD. Of the 124 biopsies performed on actionable findings in the 107 patients, findings in 79 (64%) were benign and in 45 (36%) were in situ or invasive carcinoma. Three study participants who were not recalled by the radiologist with the assistance of CAD developed cancer within 1 year of the screening mammogram and were considered to be false-negative cases. The radiologist detected 43 (90%) of the 48 total malignancies and 45 (94%) of the 48 malignancies with the assistance of CAD. CAD missed eight cancers that were detected by the radiologist, which presented as architectural distortions (n = 3), irregular masses (n = 4), and a circumscribed mass (n = 1). CAD detected two in situ cancers as a faint cluster of calcifications that had not been perceived by the radiologist and one mass that was dismissed by the radiologist, accounting for at least a 4.7% increase in cancer detection rate. Sensitivity of screening mammography with the use of CAD (94%) represented an absolute and relative 4% increase over the sensitivity of the radiologist alone (90%). Specificity of screening mammography with and without the use of CAD was 99%.Routine use of CAD while interpreting screening mammograms significantly increases recall rates, has no significant effect on positive predictive value for biopsy, and can increase cancer detection rate by at least 4.7% and sensitivity by at least 4%. This study provides "true" values for sensitivity and specificity for use of CAD in interpretation of screening mammography as measured prospectively in the context of a working clinical setting.